1. Field of the Invention
The compounds of this invention are analogues of natural prostaglandins.
Natural prostaglandins are salicyclic compounds related to prostanoic acid, the structure of which is: ##STR2## By convention, the carbon atoms of I are numbered sequentially from the carboxylic carbon atom. An important stereochemical feature of I is the trans-orientation of the sidechains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20, an orientation common to all prostaglandins. In I, as elsewhere in this specification, solid lines ( ) provide a reference plane (such as the cyclopentyl ring or the bonds among C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20); a dashed line ( ) indicates projection of a covalent bond below such reference plane (alpha-configuration); while a wedged line ( ) represents direction above such plane (beta-configuration). These conventions apply to all structural formulae subsequently discussed in this specification. In some structures, however, a swung dash or serpentine line ( ) denotes orientation of a covalent bond either above or below the plane of reference (indicated by the Greek letter xi in the nomenclature of such structures).
Natural prostaglandins have the general structure, ##STR3## in which L and M may be ethylene or cis-vinylene radicals. Prostaglandins are characterized by the substituents on the cyclopentyl ring, the position of double bonds, if any, in the cyclopentyl ring and the number of double bonds in the side chains. When the cyclopentyl ring is fully saturated, carbonyl substituted at the 9-position and hydroxyl substituted at the 11-position an E-class prostaglandin is represented (PGE) and when there is a single double bond in the sidechains, i.e., L and M in formula II are ethylene, a type-1 prostaglandin is represented. The naturally occurring E-class type 1 prostaglandins known as prostaglandin E.sub.1 or PGE.sub.1, is represented by the formula: ##STR4##
Formulae I, II and III depict the nat-isomer, i.e., the C.sub.7 -C.sub.8 bond in the alpha configuration and the C.sub.12 -C.sub.13 bond in the beta-configuration. In the ent-isomer (which does not occur in nature), the direction of the bonds at C.sub.7 -C.sub.8 and C.sub.12 -C.sub.13 is reversed.
Recent research indicates that certain prostaglandins, including PGE.sub.1 and analogues thereof, elicit biochemical and physiological effects in a variety of mammalian systems. For example, in rats PGE.sub.1 increases the release of growth hormone and in sheep it has been found to inhibit ovarian progesterone secretion. In mice, PGE.sub.1 has been found to increase thyroid activity whereas in hypophysectomized rats it has been found to stimulate stereodogenesis in the adrenal glands.
In the mammalian male reproductive system, PGE.sub.1 contracts the smooth muscle of the vas deferens and in the female reproductive system PGE compounds contract uterine smooth muscle. Prostaglandins stimulate contraction of gastrointestinal smooth muscle in vivo and in vitro. In dogs, PGE.sub.1 inhibits gastric secretion. In most mammalian respiratory tracts, PGE compounds affect in vitro preparations of tracheal smooth muscle. The human lung normally contains PGE compounds; consequently, some cases of broncial asthma may involve an imbalance in the production or metabolism of these compounds.
In addition, prostaglandins are involved in certain hematic mechanisms in mammals. For example, PGE.sub.1 inhibits aggregation of blood platelets in vitro. In a variety of mammalian cardiovascular systems, PGE compounds are vasodilators by virtue of their action or vascular smooth muscle.
Accordingly, it can be seen that prostaglandins and their analogues have broad clinical implications and research in this area continues in laboratories throughout the world.